Search Results (14,548)

Psoriatic arthritis (PsA) is a chronic inflammatory disorder affecting both the joints and skin. Beyond musculoskeletal manifestations, patients with PsA frequently exhibit alterations in lipid metabolism, contributing to an increased risk of cardiovascular disease. Dyslipidemia in PsA arises from multiple mechanisms, including systemic inflammation, insulin resistance, and imbalances in adipokines such as leptin, adiponectin, and resistin. A structured literature search was conducted in PubMed, Scopus, and Web of Science to identify relevant studies on lipid metabolism in psoriatic arthritis, and the evidence was synthesized narratively. PsA is also commonly associated with obesity and metabolic syndrome, further exacerbating dyslipidemia and cardiovascular risk. Interventions including weight loss, lifestyle modification, and anti-inflammatory treatments have been shown to improve lipid profiles and clinical outcomes. This review provides a comprehensive overview of current knowledge on altered lipid metabolism in PsA, highlighting underlying mechanisms, clinical implications, and therapeutic strategies to reduce cardiovascular risk. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide and arises from systemic metabolic dysregulation and insulin resistance. Despite its increasing prevalence, effective pharmacological interventions remain limited. Recent evidence has identified sirtuin 6 (SIRT6), an NAD⁺-dependent epigenetic regulator, as an important modulator of hepatic metabolic and stress-responsive pathways. This review summarizes current knowledge regarding the role of SIRT6 in liver physiology and MASLD pathogenesis. Accumulating evidence indicates that SIRT6 suppresses lipogenic transcriptional programs while enhancing mitochondrial oxidative capacity and fatty acid oxidation, thereby maintaining metabolic homeostasis. Beyond lipid metabolism, SIRT6 is implicated in the regulation of endoplasmic reticulum stress responses, inflammatory signaling, and chromatin accessibility, which are the processes that collectively influence hepatocellular injury and disease progression. In addition, emerging data suggest that SIRT6 modulates hepatic stellate cell activation and fibrogenic signaling pathways, thereby linking epigenetic regulation to the development of liver fibrosis. A reduction in hepatic SIRT6 expression and activity has been reported in metabolic disorders, including MASLD. We further discuss the therapeutic potential of targeting SIRT6, including the development of selective small-molecule activators and naturally derived compounds aimed at restoring SIRT6 activity. Together, the available evidence positions SIRT6 as an important regulatory node in MASLD and a promising candidate for future therapeutic intervention. Full article

Trastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a K_d value of <1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC). Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′-kinase (PI3K) pathway, cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data. Full article

Background: Diabetes mellitus is a metabolic disturbance characterized by chronic hyperglycemia, which stems from defective secretion and/or action of insulin. D-Limonene has been studied for the confirmation of its antidiabetic and antioxidant effects. This paper aims to investigate the antidiabetic and antioxidants effects of D-Limonene in an experimental model of DM1. Methods: Female Wistar rats (180–250g) received streptozotocin (STZ, 45 mg/kg) intraperitoneally. Animals with capillary glycemia ≥ 250 mg/dL were considered diabetic. D-Limonene at oral doses of 12.5 mg/kg, 25 mg/kg and 50 mg/kg was administered during 28-day treatment. Water and food intake, weight gain and capillary glycemia were evaluated. At the end of the treatment, the following biochemical parameters were assessed: serum glucose, HbA1c, urea, creatinine, AST, ALT, GGT, ALP and albumin. The oxidative stress markers were determined in plasma, erythrocytes, and aortic homogenates: malondialdehyde, nitrite, myeloperoxidase, superoxide dismutase and catalase. Results: D-Limonene (25 and 50 mg/kg) significantly reduced serum glucose, HbA1c, AST, ALT, GGT and ALP when compared to DC, as well as plasma MDA and nitrite concentrations. Interestingly, D-Limonene (25 and 50 mg/kg) decreased both plasma and aortic myeloperoxidase activities, as well as increased both erythrocytic and aortic catalase activities. Conclusions: These findings, besides a marked D-Limonene-induced hypoglycemic effect, pave the way for further studies comprising a multi-target treatment by providing benefits on hepatic and vascular complications related to the diabetic condition. Full article

Background: We previously demonstrated recapitulation of the relative hypogonadotropic hypogonadism of obesity, the Reprometabolic Syndrome (RMS), in women of normal BMI with a one-month high-fat, eucaloric diet (HFD). Objective: Assess effects of HFD on sleep, body composition and lifestyle and metabolic secondary outcomes and correlate insulin sensitivity changes with the RMS. Methods: A total of 18 normally cycling women aged 18–38 with BMI 18–24 kg/m² were enrolled for a four-month study including a eucaloric HFD (48% calories from fat) for one menstrual cycle. Activity, sleep, body composition, and the lipidome were measured in all participants. Fecal microbiome was analyzed in the last nine participants, and insulin sensitivity by two-stage hyperinsulinemic euglycemic clamp was measured before and after HFD in 15 participants. Results: Relative to the pre-diet period, BMI, activity and sleep measures did not change, except for waking after sleep onset (WASO), which appeared to decrease during and post HFD. DXA revealed statistically significant decreases in total percent fat, total fat mass, visceral fat volume, and trunk fat volume. Whole-body insulin sensitivity decreased with the HFD while adipocyte insulin sensitivity was unaffected. Insulin sensitivity changes did not correlate with change in gonadotropins or response to gonadotropin releasing hormone (GnRH). Multiple significant changes in plasma lipids were observed, including increased ceramides and glucosylceramides. Microbiome analysis revealed increased microbial diversity. Conclusions: A one-month eucaloric HFD that induced RMS in normal-weight, reproductive-aged women also induced whole-body insulin resistance (IR) and multiple lipidomics changes potentially associated with IR. These changes in IR occurred despite overall stable activity, BMI and sleep, but did not correlate with the HPO axis defects. The unexpected decrease in body fat and increase in microbial diversity may be related to specific dietary elements of the HFD. Full article

Hepatocellular carcinoma (HCC) represents a major global health challenge and the third leading cause of cancer-related mortality worldwide. Its epidemiological burden is rapidly increasing, largely driven by the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), which is now recognized as the most common chronic liver disease globally. Notably, MASLD frequently coexists with type 2 diabetes mellitus (T2DM), sharing several features, including the interplay of common genetic, metabolic, and environmental factors, thus contributing to a complex multifactorial pathogenesis. Relevantly, patients affected by both conditions represent a subgroup at particularly high risk of liver disease progression and hepatocarcinogenesis. In this population, metabolic and inflammatory disturbances act synergistically to create a pro-tumorigenic hepatic environment where insulin resistance (IR) plays a crucial role, by driving hepatic lipotoxicity, mitochondrial dysfunction, and inflammatory signaling with oxidative stress, thereby establishing a permissive environment for worsening steatosis and malignant transformation. Increasing evidence supports the concept of MASLD as a multisystem disorder reflecting the systemic nature of metabolic dysfunction. Within this framework, beyond IR, extrahepatic factors have also emerged as important contributors to steatosis progression, worsening of T2DM, and modulation of HCC risk. In particular, the gut–liver axis has gained recognition as a key regulator of hepatic homeostasis, integrating signals from the intestinal microbiota, immune responses, and metabolic pathways. Dysregulation of this crosstalk promotes systemic inflammation and metabolic imbalance, exacerbating IR and fostering a pro-oncogenic hepatic environment. This review examines the interconnected metabolic and immune mechanisms linking IR and gut–liver axis dysfunction to HCC development in patients with MASLD and T2DM, highlighting their implications for risk stratification and precision-based therapeutic strategies. Full article

Type 2 diabetes mellitus (T2DM) is driven by insulin resistance and β-cell dysfunction. While Ras GTPases are known for oncogenic signaling, emerging evidence implicates the Ras–Ral axis as a critical regulator of glucose homeostasis. This review synthesizes the distinct roles of Ras and Ral in metabolism. Ras hyperactivation promotes insulin resistance and inflammation via MAPK/PI3K pathways, whereas RalA supports GLUT4 translocation and insulin granule exocytosis. We propose a dual-pathway hypothesis: T2DM pathophysiology involves an imbalance characterized by excessive Ras signaling and insufficient Ral-mediated metabolic actions. Consequently, we explore the therapeutic potential of rebalancing this axis through combinatorial strategies, that selectively inhibit pathogenic Ras while enhancing protective Ral activity. We critically evaluate current Ras-targeted agents (e.g., farnesyltransferase inhibitors, allele-specific inhibitors) and discuss the emerging frontier of Ral-specific enhancers. Finally, we outline key translational challenges and future directions for validating this axis as a target for precision medicine in T2DM. Full article

This study aimed to investigate whether mixed heavy metal exposure (lead, cadmium, manganese, and arsenic) during pregnancy induces gestational diabetes mellitus (GDM)-like phenotypes and to explore the associated molecular alterations. We examined the effects of exposure on metabolic disturbances using a Sprague-Dawley rat model exposed to low- and high-dose mixed heavy metals, with doses selected based on biomonitoring data. The results showed that high-dose mixed heavy metal exposure significantly increased blood glucose levels in rats, elevated the area under the curve (AUC) during the oral glucose tolerance test (OGTT), and induced insulin resistance and dyslipidemia. Concurrently, pathological examinations revealed hepatocyte steatosis, inflammatory cell infiltration, and mitochondrial abnormalities in liver tissues. Transcriptomic and metabolomic analyses identified significant disruption of the glycerophospholipid metabolic pathway following heavy metal exposure, suggesting the involvement of this pathway in the observed metabolic disturbances. Lasso regression analysis identified Insig1 as a candidate gene associated with lipid metabolic alterations, a finding subsequently validated by qPCR. Overall, mixed heavy metal exposure during pregnancy was associated with GDM-like metabolic abnormalities in rats. Disruption of glycerophospholipid metabolism and altered Insig1 expression likely contribute to these effects, providing molecular evidence linking mixed heavy metal exposure to gestational metabolic dysfunction. Full article

Background: Liver inflammation and fibrosis are directly associated with non-alcoholic fatty liver disease (NAFLD). Dysregulation of the potent pro-inflammatory cytokine interleukin-1 beta (IL-1β), inducible nitric oxide synthase (iNOS), and tissue leukocyte infiltration (CD45 +ve) are connected with multiorgan injury and fibrosis. We investigated whether the induction of NAFLD can cause dysregulation in the hepatic IL-1β/iNOS and IL-1β/CD45 axes of inflammation and fibrosis, as well as in endogenous metabolites (lipids, glucose, and insulin) and apoptosis, in the presence and absence of the flavonoid quercetin. Methods: The model group of rats was fed with a high-fat and high-carbohydrate diet (HFCD) for 4 weeks. The protective group of rats was given both quercetin (50 mg/kg) and HFCD for 4 weeks. All rats were sacrificed on day 29. Results: NAFLD was induced in rats as demonstrated by dyslipidemia, hyperglycemia, insulin resistance, liver inflammation, and elevation of liver injury enzymes. NAFLD was also associated with the upregulation of hepatic IL-1β, iNOS, CD45, and apoptosis (p53). Biomarkers of fibrosis (TIMP-1 and α-SMA) were also elevated, and fibrosis was confirmed in the model group by increased collagen deposition and elevated stages of fibrosis score (Stage 1 to 2 of Brunt’s NASH classification). All these parameters were significantly (p < 0.01) modulated by quercetin treatment. Additionally, a significant (p < 0.001) correlation between IL-1β and hepatic injury parameters was observed. Conclusions: These findings suggest a potential association between NAFLD and the IL-1β/iNOS and IL-1β/CD45 axes of liver injury and fibrosis, as well as dyslipidemia, glycemia, and apoptosis, with quercetin exhibiting beneficial hepatic pleiotropic effects. Full article

Diabetes and related metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD), are increasingly recognized as diseases of inter-organ metabolic dysregulation rather than disorders of a single organ. The core of this process is the liver–pancreas axis, which integrates metabolic signals to maintain glucose and lipid homeostasis. Under physiological conditions, insulin and glucagon work together to regulate glucose production in the liver. The liver, in turn, regulates pancreatic β-cell function through hepatokines, metabolites and extracellular vesicles. Axis disorder driven by liver insulin resistance, lipid accumulation, inflammation or changes in hepatokine secretion exacerbates β-cell dysfunction, glucotoxicity and lipotoxic stress, thereby accelerating disease progression. This imbalance is involved in the pathogenesis of type 2 diabetes, type 1 diabetes, gestational diabetes, and monogenic diabetes, and makes MASLD a driving factor and early predictor of diabetes onset. This review summarizes the key molecular mechanisms behind liver–pancreas crosstalk and explores potential therapeutic strategies aimed at restoring coordinated metabolic regulation between the organs. Full article

Background: Polycystic ovary syndrome (PCOS) is a complex endocrine–metabolic disorder characterized by interconnected dysregulation of steroidogenesis and insulin signaling. Multi-target therapeutic strategies are increasingly needed to address its heterogeneous pathophysiology. Methods: An integrative approach combining transcriptomic analysis of GSE137684, including stratification of normoandrogenic and hyperandrogenic PCOS subtypes to capture androgen-related heterogeneity, network pharmacology, molecular docking, and in vitro validation was employed. Principal component analysis (PCA), differential expression analysis, and enrichment analyses were used to identify candidate genes and pathways. Molecular docking evaluated interactions between phytochemicals from Cinnamomum burmannii and Myristica fragrans and key PCOS targets. Functional validation was performed in insulin-resistant 3T3-L1 adipocytes and DHEA-induced KGN cells, assessing cell viability, lipid accumulation, glucose uptake, gene expression, and hormone levels. Results: PCA revealed partial separation between PCOS and the control samples, with PC1 and PC2 explaining 44.8% and 12.5% of variance, respectively. No genes remained significant after multiple testing correction; however, nominally significant candidates (p < 0.01) highlighted pathways related to steroidogenesis and metabolic regulation. Network analysis identified key hub genes including CYP17A1, CYP19A1, AKT1, ESR1, and MAPK1. Molecular docking demonstrated strong binding affinities, with top compounds showing binding energies up to −11.4 kcal/mol (CYP17A1) and −10.9 kcal/mol (AKT1). In vitro, cell viability remained above 80% across all tested concentrations, indicating low cytotoxicity. Treatment significantly reduced lipid accumulation and enhanced glucose uptake in insulin-resistant 3T3-L1 cells (p < 0.05). Additionally, expression of AKT1 and MAPK1 was significantly restored (p < 0.05). In KGN cells, testosterone levels were significantly decreased while the estradiol levels increased (p < 0.05), accompanied by the downregulation of CYP17A1 and upregulation of CYP19A1 (p < 0.05). The combination treatment exhibited more consistent effects across metabolic and hormonal endpoints. Conclusions:Cinnamomum burmannii and Myristica fragrans exert multi-target effects on metabolic and steroidogenic pathways relevant to PCOS. This integrative study demonstrates that transcriptomics-guided network pharmacology combined with experimental validation can identify synergistic phytotherapeutic strategies for complex endocrine disorders. Full article

Low glycemic-index foods may reduce postprandial oxidative stress by reducing postprandial glucose excursions, but the evidence for this is limited by dietary confounders. To determine whether reducing postprandial glucose per se reduces postprandial oxidative stress, overnight-fasted participants (BMI 25.0–39.9 kg/m², n = 18) consumed four test meals in random order: 75 g dextrose solution (Dex) within 5 min (bolus/noC), Dex slowly over 3.25 h (sipping/noC), bolus with 1 g vitamin C (bolus/C) and sipping with 1 g vitamin C (sipping/C). Venous blood was taken at intervals over 6 h; a standard lunch was consumed at 4 h. Sipping flattened postprandial glucose and insulin and reduced free fatty acid rebound compared to bolus (p < 0.05). Vitamin C raised serum vitamin C from ~20 to ~55 μmol/L. The total peroxyl radical trapping antioxidant potential (TRAP) increments differed after lunch, with a main effect of vitamin C at 5 h (mean ± SEM; C 70 ± 23 vs. noC −29 ± 27; p = 0.016) and main effects of rate (sipping 57 ± 25 vs. bolus −71 ± 28; p = 0.0002) and vitamin C (C 58 ± 25 vs. noC −73 ± 28; p = 0.0003) at 6 h. By multiple regression analysis, the TRAP area under the curve (AUC) was positively associated with the insulin AUC (p < 0.001) and negatively with the glucose and vitamin C AUCs (p < 0.05). The oxidized LDL increments were higher 6 h after sipping than bolus (7 ± 7 vs. −20 ± 7, p = 0.005). The oxidized LDL AUC was negatively associated with the TRAP AUC (p < 0.001). These results support the hypothesis that reducing postprandial glucose reduces postprandial oxidative stress. Full article

Conventional diabetes therapy primarily targets HbA1c using a standardized, stepwise approach, often neglecting individual clinical and diagnostic phenotypes. In this second part of our discussion, we present an alternative strategy. After phenotyping the patient, we initiate a targeted pharmacological combination therapy tailored to the individual’s underlying pathophysiology, alongside lifestyle modifications. Sulfonylureas are completely avoided in this approach. Instead, medications are selected based on their alignment with the patient’s phenotype and absence of contraindications. Early insulin therapy, for example, is particularly effective in patients with β-cell-dysfunction-driven diabetes, whereas GLP-1-supported weight reduction and glitazone therapy are more suitable for insulin-resistance-driven diabetes. For monitoring and determining when temporary therapy intensification may be necessary, we rely on a combination of functional biomarkers (intact proinsulin, adiponectin, hsCRP, and leptin) and conventional clinical parameters (HbA1c, BMI, lipids, blood pressure). Using this personalized strategy, we have consistently achieved long-term glycemic control—often maintaining normal HbA1c levels for up to 15 years in our patients so far. Full article

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide, with molecular heterogeneity complicating early detection and treatment stratification. The insulin-like growth factor (IGF) axis interacts bidirectionally with immune regulatory mechanisms in ways that shape tumor phenotype and therapeutic vulnerability. This review synthesizes evidence on how IGF signaling orchestrates immunosuppression through effects on tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, while inflammatory cytokines reciprocally modulate IGF bioavailability. Three mechanistic principles emerge: IGF binding protein 2 (IGFBP-2) functions as a central coordinator linking growth factor signaling to immune evasion through STAT3-dependent pathways driving M2 macrophage polarization and regulatory T cell differentiation; IGF–immune crosstalk varies considerably across molecular subtypes, with microsatellite-stable tumors exhibiting high reliance on IGF-I receptor-mediated immune silencing; and local paracrine IGF production increasingly dominates over systemic regulation as disease progresses. These bidirectional connections establish self-reinforcing circuits that determine whether tumors remain immunologically responsive or develop immune exclusion. Multi-marker panels incorporating IGFBP-2 alongside complementary biomarkers have shown improved diagnostic performances for early CRC detection, underscoring the need for the large-scale prospective clinical evaluation of IGF network components as biomarkers for CRC in diverse populations. The convergence of IGF signaling with checkpoint regulation suggests that combined targeting warrants investigation for resistance in tumors lacking effective immunotherapy options. Full article

Obesity is associated with menstrual dysfunction, anovulation, and infertility, particularly in women with polycystic ovary syndrome (PCOS). This narrative review summarizes evidence on the effects of bariatric surgery [focusing on sleeve gastrectomy (SG) Roux-en-Y gastric bypass (RYGB)] on female reproductive function and fertility outcomes. Developed according to SANRA (Scale for the Assessment of Narrative Review Articles) principles, a structured search of PubMed, Scopus, and Web of Science (English language; inception–30 September 2025) was conducted, using fertility-related terms (e.g., fertility, ovulation, IVF/ART, AMH, PCOS, pregnancy, live birth, time to conception) combined with bariatric surgery terms (SG/VSG, RYGB, metabolic/bariatric surgery, and weight loss surgery). Guidelines from IFSO, BOMSS, and ASMBS were also reviewed. Findings were synthesized narratively. Across mainly observational studies, bariatric surgery is associated with improved menstrual regularity, increased ovulation, reduced hyperandrogenism, and improved insulin sensitivity, with higher conception rates reported after substantial weight loss. AMH responses are inconsistent across studies and their clinical significance remains uncertain. SG and RYGB appear to improve fertility-related outcomes in women with obesity. Programming of pregnancy and nutritional monitoring are critical. In conclusion, long-term, standardized reproductive endpoints are needed to clarify bariatric surgery-associated effects during pregnancy. Full article